The present invention is drawn to processes for coupling phenols and optionally substituted cycloalkyls.
3-Cyclopentyloxy-4-methoxybenzaldehyde (formula I) is a key intermediate in the preparation of compounds that are useful in the treatment of asthma, inflammatory disorders including psoriasis, proliferative skin disease, Crohns disease, urticaria, rhinitis, arthritis and neurogenic inflammation, and depression.

One current preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde includes alkylating 3-hydroxy-4-methoxybenzaldehyde (isovanillin) with cyclopentyl bromide in a solvent such as N,N-dimethylformamide (DMF), acetone or acetonitrile (MeCN) in the presence of anhydrous potassium or cesium carbonate. However, product isolation from the reaction mixture is cumbersome, especially on a large scale. Specifically, in order to isolate 3-cyclopentyloxy-4-methoxybenzaldehyde, an aqueous work-up must be performed including the addition of water, extraction, separation, and drying to give variable yields of 3-cyclopentyloxy-4-methoxybenzaldehyde. The compound of formula I can then be utilized in further reactions.
The solvents utilized during alkylation of isovanillin are also incompatible with the reagents used in certain subsequent reactions. For example, DMF, acetone or MeCN can react with organometallic reagents, ylides, glycidyl esters, and carbanions, among reagents. These organometallic reagents, ylides, glycidyl esters, and carbanions usually require anhydrous conditions and anhydrous solvents, such as tetrahydrofuran (THF). It is therefore necessary to isolate 3-cyclopentyloxy-4-methoxybenzaldehyde from the DMF, acetone, or MeCN prior to performing subsequent steps.
What is needed in the art are other methods for preparing compounds of formula I.